Our overall goal is to take advantage of the extraordinary activity-dependent plasticity of the mature motor systems, to achieve significant repair of the damaged corticospinal tract (CST) after brain or spinal cord injury. We aim to promote the motor functions of the CST spared after an incomplete injury. These spared connections are sparse and weak; by themselves, they cannot exert significant motor control. Our rat studies use a unilateral pyramidal tract lesion (PTX) that eliminates all CST axons from one motor cortex (M1). This lesion eliminates most of the CST on the affected contralateral spinal cord, with only sparse ipsilateral CST axons remaining. PTX produces significant sprouting from the spared ipsilateral CST, which we hypothesize is adaptive because M1 electrical stimulation after injury promotes this sprouting, leading to motor recovery. PTX also produces proprioceptive afferent sprouting and spinal neuron changes that we hypothesize are maladaptive, because they can lead to spasticity and weakness. Aim 1 will determine the activity dependence of spinal reactive changes after unilateral CST lesion. We hypothesize that activity loss, not just the physical loss of connections, is an important trigger for reactive changes after injury. We will unilaterally inactivate M1 to determine the activity dependence of CST changes (Aim 1A) and impairments in spinal interneuron and motoneuron function (Aim 1B). We will determine the effects of optogenetic activation of spinal interneurons on reactive spinal changes produced by M1 inactivation (Aim 1C). In Aim 2 we will determine the role of spinal cord activation in abrogating maladaptive segmental changes after injury and in promoting the motor functions of the spared CST. We hypothesize that stimulating spinal circuits after injury will increase their response to signals from spared CST axons. Aim 2A directly tests this hypothesis using the optogenetic approach to activate spinal interneurons with temporal precision, and trans-spinal direct current stimulation (tsDC), an activation approach with translational potential. Spinal stimulation provides segmental activation after CST loss. In Aim 2B we will determine if tsDC promotes sprouting of spared CST connections, abrogates maladaptive spinal changes and, together, strengthens the M1-to-muscle pathway. In Aim 2C we will determine if tsDC promotes behavioral recovery after PTX. Aim 3 will harness short-term functional M1 plasticity and spinal activation in combination, to strengthen CST connections, enhance CST outgrowth, and promote motor function after injury. We combine top down M1 activation with bottom up spinal activation to achieve novel therapeutic insights. We hypothesize that potent short-term plasticity, produced by high-frequency patterned M1electrical stimulation, strengthens and produces sprouting of spared CST axons. Augmented CST signals will now be amplified by spinal activation. In Aim 3A we study the acute effects of patterned M1 stimulation, alone and combined with tsDC, on CST transmission and M1 intracortical circuits. Aim 3B will determine if CST sprouting, connection strength, and locomotor recovery are promoted by chronic patterned M1 stimulation, and if tsDC affects the response. Aim 3C combines cortical and spinal stimulation to restore distal forelimb motor function in a clinically relevant cortical lesion model.